Cancer Pharmacology Flashcards
1
Q
Principles of Chemo
A
- use of chemical agents to kill or inhibit cancer cells
- the ultimate goal of chemotherapy is a cure (long-term, disease-free survival); if a cure is not attainable, at least palliation (attenuation of symptoms)
- chemotherapy is given to cancer patients whose neoplasms are not amenable to surgery or radiation therapy; also used as a supplemental treatment following surgery/radiation therapy to prevent metaastasis
- most chemotherapeutic agents interfere with cell proliferation and/or induce apoptosis; rapidly dividing cancer cells are more sensitive to chemotherapy than normal cells
2
Q
Log Kill Hypothesis
A
- a given dose of drug kills a constant fraction of cells rather than a constant number of cells (first-order kinetics)
- cell viability decreases with increased drug concentration
- different drugs have different effects on cell viability
3
Q
Principles of combination therapy
A
- each drug used in the regiment should have individual anticancer actions
- drugs that act by different mechanisms should be considered
- the combination therapy should have additive or synergistic effects
- drugs with different (non-overlapping) dose-limiting toxicities should be used
- several cycles (6-8) of treatment should be given
4
Q
Advantages of combination therapy
A
- provide maximum cell killing with less toxicity
- effective against heterogenous cell populations present in tumors
- reduces the changes of development of resistant clones
5
Q
Combination Regimens
A
- ABVD- Hodgkin’s disease
- CHOP- Non-Hodgkin’s lymphoma
- MOPP- Hodgkin’s disease
- CMF- Breast cancer
- FEC- Breast cancer
6
Q
Drug resistance
A
- must tumors acquire drug resistance after prolonged administration of the drug
- decreased cellular uptake
- abnormal transport of the drug (rapid efflux by P-glycoprotein)
- increased cellular inactivation (binding/metabolism)
- altered target protein
- reduced affinity for the drug
- enhanced repair of DNA damage
7
Q
Toxicity
A
- chemotherapeutic agents aimed at killing cancer cells also affect normal cells undergoing rapid proliferation (eg BM, GI mucosa, hair follicles)
- common side effects: neutropenia, thrombocytopenia, anemia, nausea, vomiting, stomatitis, alopecia (hair loss), leukemia/myelodysplasia in long term treatment with chemo agents
8
Q
Cell cycle and anti-cancer drugs
A
- cell cycle specific drugs (e.g. antimetabolites, vinca alkaloids)- active in a specific phase of the cell cycle, effective when a large proportion of tumor cells are proliferating (ie high growth fraction tumors); such as hematologic malignancies
- cell cycle-nonspecific drugs (alkylating agents)- kill both cycling and noncycling tumor cells, effective against both low growth fraction tumors, such as solid tumors as well as high growth fraction tumors
9
Q
Anticancer Drugs
A
- alkylating agents
- antimetabolites
- DNA intercalating agents
- microtubule inhibitors
- topoisomerase inhibitors
- hormones and their antagonists
- miscellaneous agents (e.g. antibodies, kinase inhibitors)
10
Q
Alkylating Agents Overview
A
- compounds with the ability to transfer an alkyl group to DNA
- promote cross-linking of DNA strands resulting in DNA damage
- cell cycle non-specific agents- act on proliferating and resting cells
- evolved from chemical warfare agents (mustard gas)
- first agents use clinically to treat cancer patients; Goodman and Gilman initated clinical studies of nitrogen mustards in patients with lymphoma in 1942
11
Q
Toxicities of Alkylating Agents
A
- dose-related bone marrow suppression (neutropenia, thrombocytopenia, anemia)
- mucosal toxicity (oral mucosal and GI ulceration)
- nausea and vomiting
- toxic effects on male and female reproductive system
- highly carcinogenic; increased risk of secondary leukemia
12
Q
Specific Alkylating Agents
A
1) Nitrogen Mustards- mechlorethamine, cyclophosphamide, ifosfamide
2) Nitrosoureas- Carmustine, Lomustine
3) Triazenes- Dacarbazine, Temozolomide
4) Platinum Analogs- Cisplatin, Carboplatin, Oxaliplatin
13
Q
Mechlorethamine
A
- nitrogen mustards
- most reactive
- first clinically used nitrogen mustard; used in combination reginmen MOPP
- used topically for treatment of cutaneous T cell lymphoma
- Toxicity: severe nausea and vomiting, myelosuppression
14
Q
Cyclophosphamide/Ifosamide
A
- nitrogen mustards
- prodrugs that must be converted to active alkylating metabolites by P450
- can be taken orally and they have a relatively long pasma half life
- very broad clinical spectrum, component of many combination regimens (CHOP, CMF, FAC, FEC)
- used for treatment of non-Hodgkin’s lymhoma, breast, lung and ovarian cancer
- Ifosamide- sarcoma and testicular cancer
- Toxicity: nausea, vomiting, myelosuppression
- hemorrhagic cystitis (due to accumulation of toxic metabolite acrolein); administration of MESNA (2-mercaptoethane sulfonate) minimizes this problem
15
Q
Nitrosoureas
A
- type of alkylating agent
- Carmustine and Lomustine
16
Q
Carmustine and Lomustine
A
- nitrosoureas (alkylating agent)
- therapeutic uses- they are highly lipophilic, used for treatment of meningeal leukemias and brain tumors
- Toxicity- severe nausea and vomiting, profound myelosuppression, renal toxicity, pulmonary fibrosis
17
Q
Triazenes
A
- Dacarbazine and Temozoi
- pro-drugs, monoalkylators
18
Q
Dacarbazine, Temozolomide
A
- triazenes (type of alkylating agent)
- pro-drugs
- therapeutic uses- decarbazine is a compoent of ABVD regiment used for treatment of Hodgkin’s disease
- Temozolomide has shown activity against malignant glioma
- toxicity- nausea and vomiting, myelosuppression, flu-like symptoms
19
Q
Platinum Analogs
A
- Cisplatin, Carboplatin, oxaliplantin
- inorganic platinum derivatives; covalently bind to nucleophilic sites (N7 of guanine) on DNA
- form intrastrand and intersrand cross links
20
Q
Cisplatin
A
- Platinum Analogs
- efficacy against a wide range of neoplasms
- used for treatment of testicular, ovarian, cervical and bladder cancers
- nephrotoxicity (renal tubular damage and necrosis); ototoxicity (hearing loss); peripheral neuropathy; nausea and vomiting; myelosuppression
21
Q
Carboplatin
A
- platinum analog
- ovarian cancer
- less toxic and less reactive
- thrombocytopenia is dose-limiting
22
Q
Oxaliplatin
A
- platinum analog
- used in combo with 5-FU for gastric and colorectal cancer
- unique toxicity- cold-induced acute peripheral neuropathy
23
Q
Antimetabolites
A
- structural analogs of endogenous folates, purines and pyrimidines
- inhibit enzymes required for nucleotide synthesis or complete with endogenous nucleotides in DNA or RNA synthesis
- act specifically in the DNA synthesis (S) phase of the cell cycle; thus considered as cell cycle specific (ccs) drugs
24
Q
Antimetabolite types
A
1) Folate Analogs- methotrexate, pemetrexed
2) Pyrimidine Analogs- 5-Flurouracil, Cytarabine, Gemcitabine
3) Purine Analogs- 6- Mercaptopurine
25
Q
Folate Analogs
A
- type of antimetabolite
- Methotrexate (MTX)
26
Q
Methotrexate
A
- most widely used antimetabolite in cancer chemotherapy
- produced first striking remission of leukemia
- produced first cure of solid tumor (choriocarcinoma)
- inhibits the enzyme dihydrofolate reductase
- effective in treating childhood ALL, choriocarcinoma, osteosarcoma, breast cancer, head and neck cancer
- usually given orally; administered intrathecally for meningeal leukemia
- toxicity- bone marrow toxicity (myelosuppression), GI toxicity (oral ulceration, stomatitis, renal toxicity (MTX can crystallize in the urine and cause renal damage), hepatotoxicity (long-term use of MTX may lead to fibrosis or cirrhosis
- Mechanisms of Resistance- reduced drug uptake by neoplastic cells, increased production of DHPR (gene amplification), decreased affinity of DHFR for MTX
27
Q
Pemetrexed
A
- a multi-targeted folate analog, which inhibit both DHFR and thymidylate synthetase
- approved fir treatment of non-small cell lung cancer and mesothelioma, colon and pancreatic
28
Q
Leucovorin rescue
A
- prevention of the toxic effects of MTX by Leucovorin
- N-5 formyltetrahydrofolate) is administered to the patient several hours after an otherwise lethal dose of methotrexate
- the malignant cells are killed selectively, while the normal cells are rescued by the folinic acid.
- one hypothesis is that tumor cells cannot uptake folinic acid (Leucovorin) whereas normal cells can uptake folinic acid and bypass the requirement of DHFR
29
Q
Pyrimidine Analogs
A
- 5-Fluorouracil
- Cytarabine
- Gemcitabine
30
Q
5-Fluorouracil (5-FU)
A
- a pro-drug requiring enzymatic conversion into active metabolites 5-FdUMP) and (5-FdUTP) to exert its cytotoxic activity
- 5-dUMP inhibits thymidylate synthase and prevents the synthesis of thymidine, a major building block of DNA
- FdUTP is incorporated into RNA by RNA polymerase and interferes with RNA function
- therapeutic uses- must be given IV due to rapid metabolic degradation in the gut and liver, used as a compnent of combo regiments for treatment of breast, colorectal, gastric, head and neck, cervical and pancreastic cancers, used topically for basal cell carinomas
- toxicity- anorexia and nausea, mucosal ulcerations, stomatits and diarrhea, thrombocytopenia and anemia, hand-foot syndrome-erythema, senesitivity to the palms and soles, cardiac toxicity- acute chest pain
31
Q
Cytarabine (Ara-C)
A
- type of pyrimidine analog
- analog of 2’ deoxycytidine (natural ribose is replaced by D-arabinose)
- converted to Ara-CMP by deoxycytidine kinase
- Ara-CMP is subsequnetly converted to Ara-CTP, which competes swith dCTP for incorporation into DNA by DNA polymerase
- when incorporated into DNA, Ara-CTP inhibits DNA synthesis
- therapeutic uses- most effective for treatment of AML, also useful for ALL and blast phase CML
- toxicity- severe myelosuppression
- GI tract toxicity (ulceration, stomatits, diarrhea)
32
Q
Gemcitabine
A
- type of pyrimidine analog
- a difluoro analog of deoxycytidine (dFdC)
- converted to active di- and tri- phosphate metabolites (dFdCDP, dFdCTP)
- dFdCCP inhibits ribonucleotide reductase, resulting in the depletion of deoxyribonucleotides necessary for DNA synthesis
- dFdCTP competes with dCTP for incorporation into DNA and leads to termination of DNA synthesis
- more effective in treating solid tumors than cytarabine
- therapeutic= used as a first-line treatment for pancreatic carcinoma, it is also effective against non-cell lung cancer, ovarian, bladder, esophageal and head and neck cancer
- toxicity- myelosuppression (leukopenia, thrombocytopenia, anemia), flu-like syndrome
33
Q
Purine analogs
A
- a treatment for hyperuricemia and gout
- later purine analogs have been found useful for treatment of cancer
- 6- Mercaptopurine
34
Q
6-Mercaptopurine
A
- a pro-drug
- requires enzymatic conversion to ribonucleotide by HGPRT
- it causes a reduction in purine levels resulting in inhibition of DNA and RNA synthesis in tumor cells
- it is prodrug that must be metabolized by HGPRT to the ribonucleotide-6-thioionsinic acid (TIMP)
- TIMP inhibits the first step of the de novo synthesis of the purine base
- TIMP also blocks formation of AMP and xanthinylic acid from inosinic acid
- also TIMP is converted to thio guanine ribonucleotides, which are incorporated into DNA and RNA resulting in inhibition of DNA and RNA synthesis
- therapeutic uses- used primarily to maintain remission in patients with ALL
- Toxicity- bone marrow suppression, hepatotoxicity in prolonged use of 6-MP
- Mechanism of Resistance- decreased expression of HGPRT, decreased drug transport
- drug interaction with allopurinol- allopurinol inhibits xanthine oxidase and thereby increases plasma MP levels (you need to decrease the dose of 6-MP in patients receiving allopurinol to avoid accumulation of the drug and exacerbation of toxicities
35
Q
DNA Intercalating Agents
A
- anti-tumor antibiotics
- derived from various strains of Streptomyces
- bind to DNA through intercalation between specific bases and block synthesis of DNA, RNA or both
- cause DNA strands break and interfere with cell replication
36
Q
Dactinomycin
A
- first anticancer antibiotic derived from Streptomyces
- intercalates between adjacent G-C base pairs
- interferes with DNA-dependent RNA polymerase, causing inhibition of DNA transcription
- causes single strand breaj
- used for treatment of rhabdomyosarcoma, Wilm’s tumor and Ewing’s sarcoma in children
- toxicity: anorexia, nausea and vomiting, may cause hematopoietic suppression with pancytopenia
37
Q
Anthracyclins
A
- DNA intercalating agents
- Daunorubicin, Doxorubicin, Epirubicin, Idarubicin
- they intercalate between DNA base pairs
- anthracyclines are reduced to intermediates that donate electrons to oxygen to form superoxide
- superoxide then reacts with itself to make hydrogen peroxide which is cleaved in the presence of iron to form the destructive hydroxyl radical that cleaves DNA
38
Q
Doxorubicin
A
- also known as adriamycin
- has broad clinical spectrum; one of the most widely used anticancer drugs
- used for treatment of sarcomas, breast and lung carcinomas and lymphomas
- toxicity- dose dependent cardiotoxicity (cardiomyopathy), neutropenia, stomatitis, alopecia
39
Q
Daunorubicin and Idarubicin, Epirubicin and Mitoxantrone
A
- other anthracyclines
- Daunorubicin and Idarubicin- used in combination with Ara-C for treatment of AML
- Epirubicin- used in combo regimen for treatment of metastatic breast cancer
- Mitoxantrone- less cardiotoxic than other anthracyclines, approved from treatment of AML and late stage multiple sclerosis
- -toxicity- dose dependent cardiotoxicity (cardiomyopathy), neutropenia, stomatitis, alopecia
40
Q
Bleomycin
A
- DNA intercalating Agent
- mixture of two peptides obtained from streptomyces
- binds to DNA, induces single and double stranded DNA breaks in the G2 phase of the cell cycle
- therapeutic uses- used as a component of PEB combo regimen for treatment of testicular carcinomas or as a component of ABVD regimen for Hodgkin’s disease
- also effective against squamous cell carcinomas
- toxicity- severe dose-related pulmonary toxicity (pulmonary fibrosis), minimally myelosuppressive, cutaneous toxicity (hyperpigmentation, hyperkeratosis, erythema)
41
Q
Microtubule Inhibitors
A
- plant natural products
- bind tubulin, interfere with microtubule function
- causes mitotic arrest (M phase of cell cylcle)
- Vinca Alkaloids- Vinblastine, Vincristine
- Taxanes- Paclitaxel, Docetaxel
42
Q
Vinca Alkaloids
A
- derived from the periwinkle plant Vinca rosea
- bind to tubulin, and prevent polymerization of tubulin into microtubules
43
Q
Vinblastine
A
- vinca alkaloid (microtubule inhibitor)
- component of ABVD for Hodgkin’s lymphoma
- toxicity- myelosuppression, nausea, vomiting
- resistance- amplification of P-glycoprotein; mutations in tubulin resulting in reduced binding of the drugs to their target
44
Q
Vincristine
A
- vinca alkaloid (microtubule inhibitor)
- used with glucocorticoids in the treatment of childhood ALL; also a component of MOPP regimen for Hodgkin’s lymphoma
- toxicity- dose-limiting neurotoxicity (peripheral neuropathy) but relatively low toxicity in the bone marrow
- resistance- amplification of P-glycoprotein; mutations in tubulin resulting in reduced binding of the drugs of their target
45
Q
Taxanes
A
- microtubule inhibitors
- Paclitaxel and Docetaxel
- alkaloids derived from the yew trees
- Paclitaxel- bark, Docetaxel- needles
- bind to to tubulin and prevent depolymerization of microtubules which is necessary from chromosome desegregation during mitosis
46
Q
Paclitaxel
A
- microtubule inhibitor- taxane
- components of regimen used for treatment of metastatic breast, ovarian, lung and head and neck cancers
- toxicity- neutropenia, peripheral neuropathy, hypersensitivity reactions
47
Q
Docetaxel
A
- components of regimen used for treatment of metastatic breast, ovarian, lung and head and neck cancers
- useful against hormone- refractory prostate cancer
- toxicity- neutropenia, peripheral neuropathy, hypersensitivity reactions
48
Q
Topoisomerase Inhibitors
A
- topoisomerases mediate DNA strand breakage and resealing during replication or transcription of DNA
- Top1 breaks and reseals single stranded DNA, whereas Top II breaks and reseals double stranded DNA
- inhibitors of topoisomerases cause permanent DNA strand breaks by preventing the resealing of nicked strands of DNA
- Epipodophyllotoxin- Etoposide, Teniposide
- Camptothecin Analogs- Irinotecan, Topotecan
49
Q
Epipodophyllotoxins
A
- Etoposide, Teniposide
- inhibit Top II
50
Q
Etoposide
A
- Top II inhibitor, epipodophyllotoxin
- broad clinical spectrum; used for treatment of testicular carcinoma, lung cancer, and non-Hodgkin;s lymphoma
- toxicity- dose-limiting myelosuppression (neutropenia), oral mucositis
51
Q
Teniposide
A
- Top II inhibitor, epipodophyllotoxin
- mainly used for acute lymphoblastic leukemia ALL
- toxicity- dose limiting myelosuppression (neutropenia), oral mucositis
52
Q
Camptothecin Analogs
A
- irinotecan, topotecan
- inhibit Top I
53
Q
Irinotecan
A
- inhibit Top I
- camptothecin analog
- approved for treatment of advanced colorectal cancer; also used for lung, ovarian, cervical and brain tumors
- toxicity- severe neutropenia, severe diarrhea
54
Q
Topotecan
A
- inhibit TopI
- camptothecin analog
- indicated for treatment of ovarian and small cell lung cancer
- toxicity- severe neutropena, severe diarrhea
55
Q
When is hormonal therapy useful?
A
- lymphomas and leukemia
- breast cancer
- prostate cancer
56
Q
Glucocorticoids
A
- have shown cytotoxic effects on lymphocytes
- they inhibit mitosis in lymphocytes
- they are relatively well tolerated and do not induce myelosuppression
57
Q
Prednisone
A
- glucocorticoids (inhibit mitosis in lymphocytes)
- prednisone plus vincristine produce remission in patients with ALL
- also a component of combination regiments (MOPP and CHOP) for Hodgkin’s and non-Hodgkin’s lymphomas
58
Q
Dexamethsaone
A
- glucocorticoid (cytotoxic and inhibit mitosis in lymphocytes)
- used to reduce edema following radiation therapy
59
Q
Hormone Therapy for Breast Cancer
A
- breast cancer is usually estrogen dependent and can be suppressed by administration of estrogen antagonists
- Selective Estrogen-Receptor Modulators (SERMs): Tamoxifen
- Selective Estrogen-Receptor Down regulators (SERDs): Fulvestrant
- Aromatase Inhibitors- Aminoglutethamide, Anastrozole, Letrozole, Exemestane
60
Q
Tamoxifen
A
- competes with estradiol for binding to the ER, resulting in non-functional hormone receptor complex
- used for treatment of ER- positive early stage and metastatic breast cancer
- used for prevention of breast cancer in high risk patients (family history)
- toxicity- hot flushes, hair loss, nausea and vomiting, weak agonist in endometrium; increased risk of endometrial cancer and thromboembolism
61
Q
Fulvestrant
A
- first FDA approved SERD (Selective Estrogen-receptor downregulators)
- binds to ER with a much higher affinity (>100 fold) than tamoxifen
- reduces ER expression
- approved for postmenopausel women with ER- positive metastatic breast cancer
62
Q
Aromatase Inhibitors
A
- inhibit the enzyme aromatase, which is necessary for estrogen synthesis
- Als cause profound estrogen deprivation in postmenopausal women
- aminoglutethamide, Anastrozole, Letrozole, Exemestane
63
Q
Aminoglutethamide
A
- aromatase inhibitors
- a first generation Al; it has beneficial effects against breast cancer
- has signficant toxicity; replaced by third generation Als
64
Q
Anastrozole, Letrozole, Exemestane
A
- third generation Al; potent and selective inhibitor of aromatase
- Anastrozole and Letrozole are non-steroidal reversible inhibitors of aromatase
- Exemestate is a steroidal inhibitor of aromatase; it competes with the natural substrate androstenedione; irreversibly inactivates aromatase
- 3rd generation- used for treatment of early and late stage breast cancer
- have replaced tamoxifen as first-line therapy for postmenopausal ER+ breast cancer
65
Q
Hormone Therapy for Prostate Cancer
A
- androgen deprivation therapy (ADT) through either surgical or medical castration is useful for treatment of advanced prostate cancer
- Leuprolide, Goserelin
- Flutamide, Bicalutamide
66
Q
Leuprolife, Goserelin
A
- hormone for prostate cancer
- are GnRH analogs
- bind to GnRH receptor and inhibit the release of FSH and LH, resulting in reduced testicular production of testosterone
- do not inhibit adrenal androgen synthesis
67
Q
Flutamide, Bicalutamide
A
- hormone for prostate cancer
- are non-steroidal androgen-receptor (AR) blockers
- compete with natural hormone for binding with the AR
68
Q
Hydroxyurea
A
- Misc cancer drug
- inhibits ribonucleotide reductase, which catalyzes the conversion of ribonucleotides to deoxyribonucleotides
- useful for treatment of MPDs (CML, PV, ET) and sickle cell disease
69
Q
Retinoids
A
- all trans retinoic acid is very useful in the treatment of acute promyleocytic leukemia (APL)
- it induces differentiation in leukemic promyleocytes and produces remission in patients with APL
70
Q
Arsenic Trioxide
A
- misc agents
- a heavy metal toxin highly effective in the treatment of relapsed APL
71
Q
Thalidomide
A
- misc agents
- inhibits the production of IL-6, which is a growth factor for myeloma cells
- inhibits TNFalpha signaling (immunodulatory effects)
- exhibits antiangiogenic activity
- activates the apoptotic pathways
- approved for treatment of multiple myeloma
72
Q
Interferon-alpha
A
-approved for treatment of hairy cell leukemia, CML and AIDS-related Kaposi’s sarcoma
73
Q
Tyrosine Kinase Inhibitors
A
- imatinib (Abl inhibitor) for treatment of CML, also inhibits PDGFR and c-kit
- gefitinib/erlotinib *EGFR inhibitor) for treatment of non-small cell lung cancer
74
Q
Monoclonal Antibodies
A
- Trastuzumab for treatment of metastatic HER2+ breast cancer
- Cetuximab (a mAB against ErbB1) for treatment of metastatic colon cancer)
